Project Summary - Baraban Identification of more effective strategies to prevent and treat drug addiction is critically dependent on advances in deciphering the signaling pathways that mediate and regulate the behavioral effects of drugs of abuse. Recent studies indicate that the microRNA system plays a prominent role in this process. However, we are only beginning to understand its impact on neuronal signaling. In recent studies, we have found that the translin/trax RNase complex mediates degradation of a subset of microRNAs. Accordingly, to advance our understanding of the role of the microRNA system in dopamine signaling, we have checked whether translin KO mice display altered behavioral responses to cocaine. We have found that the ability of cocaine to increase locomotor activity is impaired in these mice. Furthermore, microdialysis studies revealed that cocaine's ability to elevate DA in the nucleus accumens is blunted in translin KO mice. In addition, fast scan cyclic voltammetry studies indicate that translin deletion blocks cocaine's ability to potentiate evoked release of DA without interfering with its ability to block the dopamine transporter. As recent studies have focused attention on the poorly understood ability of cocaine to potentiate evoked DA release as playing a key role in mediating its reinforcing properties, we plan to conduct studies aimed at understanding how translin deletion impairs this effect. In particular, we will assess whether this phenotype is: 1) due to loss of translin/trax RNase activity, and 2) due to loss of translin from DA neurons. Furthermore, we will use self-administration assays to assess whether translin deletion impairs the reinforcing properties of cocaine.